Articles

Lymph Node Dissection in Renal Cell Carcinoma eulogo1

By: Umberto Capitanioa lowast , Frank Beckerb, Michael L. Blutec, Peter Muldersd, Jean-Jacques Patarde, Paul Russof, Urs E. Studerg and Hein Van Poppelh

Published online: 01 December 2011

Keywords: Renal cell cancer, Renal cell carcinoma, Kidney cancer, Lymphadenectomy, Lymph node excision, Lymphatic metastases, Nephrectomy, Imaging, Complications

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Abstract

Context

Although lymphadenectomy (lymph node dissection [LND]) is currently accepted as the most accurate and reliable staging procedure for the detection of lymph node invasion (LNI), its therapeutic benefit in renal cell carcinoma (RCC) still remains controversial.

Objective

Review the available literature concerning the role of LND in RCC staging and outcome.

Evidence acquisition

A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in RCC. Keywords included kidney neoplasms, renal cell cancer, renal cell carcinoma, kidney cancer, lymphadenectomy, lymph node excision, lymphatic metastases, nephrectomy, imaging, and complications. The articles with the highest level of evidence were identified with the consensus of all of the collaborative authors and were critically reviewed. This review is the result of an interactive peer-reviewing process by an expert panel of co-authors.

Evidence synthesis

Renal lymphatic drainage is unpredictable. The newer available imaging techniques are still immature in detecting small lymph node metastases. Results from the European Organization for Research and Treatment of Cancer trial 30881 showed no benefit in performing LND during surgery for clinically node-negative RCC, but the results are limited to patients with the lowest risk of developing LNI. Numerous retrospective series support the hypothesis that LND may be beneficial in high-risk patients (clinical T3–T4, high Fuhrman grade, presence of sarcomatoid features, or coagulative tumor necrosis). If enlarged nodes are evident at imaging or palpable during surgery, LND seems justified at any stage. However, the extent of the LND remains a matter of controversy.

Conclusions

To date, the available evidence suggests that an extended LND may be beneficial when technically feasible in patients with locally advanced disease (T3–T4) and/or unfavorable clinical and pathologic characteristics (high Fuhrman grade, larger tumors, presence of sarcomatoid features, and/or coagulative tumor necrosis). Although node-positive patients often harbor distant metastases as well, the majority of retrospective nonrandomized trials seem to suggest a possible benefit of regional LND even for this group of patients.

In patients with T1–T2, clinically negative lymph nodes and absence of unfavorable clinical and pathologic characteristics, regional LND offers limited staging information and no benefit in terms of decreasing disease recurrence or improving survival.

Take Home Message

In very low-risk renal cell carcinoma patients (cT1–T2N0 and no unfavorable clinical or pathologic characteristics), regional lymphadenectomy offers no benefit in terms of disease recurrence or survival. In intermediate- and high-risk patients, the majority of retrospective nonrandomized trials seem to suggest a possible benefit of lymphadenectomy on cancer-specific survival.

Keywords: Renal cell cancer, Renal cell carcinoma, Kidney cancer, Lymphadenectomy, Lymph node excision, Lymphatic metastases, Nephrectomy, Imaging, Complications.

1. Introduction

Although lymphadenectomy (lymph node dissection [LND]) represents the most accurate and reliable staging and therapeutic procedure for the detection of lymph node invasion (LNI) in bladder and prostate cancer patients [1] and [2], the value of LND in patients with renal cell carcinoma (RCC) still remains controversial. To date, no data have clearly demonstrated which candidates should undergo LND and which template should be used for LND in RCC surgical management. Consequently, many urologists have abandoned systematic and standardized LND at the time of nephrectomy because of the lack of a proven benefit.

In this context, in 2008 the European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Group published the final results of a randomized phase 3 trial showing no survival advantage for clinically node-negative patients treated with nephrectomy alone compared with nephrectomy with LND [3]. However, although the EORTC 30881 trial represents the only available prospective randomized study, some flaws regarding the study design partially undermined the clinical applicability of its results [4]. The most important criticism was that the majority of the patients included in the trial had low-stage tumors with a negligible risk for nodal involvement [4]. As has been demonstrated in other urologic settings, RCC patients who may benefit most from LND are those with intermediate- and high-risk disease [4]. However, despite the large number of RCC patients included in EORTC 30881, the number of high-risk patients was too small to allow for a final oncologic statement regarding the benefit of performing LND [4]. Finally, EORTC 30881 could not address the crucial point of where and to what extent LND should be performed, because precise information regarding the template for LND used or the number of lymph nodes removed was lacking.

The objective of the current study was to review the available literature concerning the prevalence and prognostic implication of LNI in the RCC setting, as well as the indications and morbidity associated with performing LND at the time of nephrectomy.

2. Evidence acquisition

A Medline search was conducted to identify original articles, review articles, and editorials addressing the role of LND in kidney cancer. Keywords included kidney neoplasms, renal cell cancer, renal cell carcinoma, kidney cancer, lymphadenectomy, lymph node excision, lymphatic metastases, nephrectomy, imaging, and complications. Links to related articles and cross-reading of citations in related articles were surveyed. The articles with the highest level of evidence (1b, 2a, 2b, 2c, 3a, and 3b) were identified and analyzed, and they represent the basis of this review article. This review is the result of an interactive peer-reviewing process by an expert panel of co-authors.

3. Evidence synthesis

3.1. Anatomic pattern of the renal regional lymph nodes

Two major aspects must be considered: (1) the presence of many possible different lymphatic routes in normal retroperitoneal anatomy [5] and (2) the unpredictable effects of local progression of the tumor, which may induce neovascularization, blockage of lymphatic vessels by cancer cells, collateral lymphatic drainage, and invasion of tissue with different lymphatic drainage (eg, perinephric fat [6]).

Since Parker's anatomic studies in 1935, several reports have confirmed the unpredictable anatomy of kidney lymphatic drainage (Table 1) [5] and [7]. Typically, the most frequent lymphatic landing sites are paracaval and retrocaval nodes (right kidney), para-aortic and preaortic nodes (left kidney), and interaortocaval nodes (both right and left kidneys); however, in one-third of cases, renal lymphatics have been found connecting directly to the origin of the thoracic duct, without crossing any lymph nodes [7]. Isolated metastases have also been found in the ipsilateral iliac nodes and in the supraclavicular nodes [8]. Saitoh et al. described extremely wide variation in the anatomic localization of lymph node metastases from RCC [9]. Interestingly, the ipsilateral renal hilar area, which represents the most sampled area during limited LND in RCC cases, showed LNI in only 7% of the cases, whereas para-aortic sites showed metastases in 26.8% of cases and supraclavicular sites in 20.7% of cases [9]. At the end of the 1990s, Johnsen and Hellsten retrospectively studied 554 autopsies of patients who died from other causes but showed evidence of kidney cancer at autopsy. Lymph node metastases were found in 80 men (14%), but only 5 men showed exclusively paracaval or para-aortic positive nodes [10]. From these data, it could be speculated that systematic LND would have been potentially curative in only 7% of all patients with pN+ disease (0.9% considering all kidney cancers) [10].

Table 1 Primary landing sites for kidney drainage (anatomic studies) or lymph node invasion in renal cell carcinoma (pathologic studies)

Author Study design Cases with RCC, no. Landing sites
Hilar, % Regional areas Distant areas
Precaval/paracaval, % Interaortocaval, % Para-aortic, % Iliac, % Supraclavicular, %
Johnsen and Hellsten et al. [10] Autopsy 554 NA NA NA NA NA 0.2
Hulten et al. [8] Pathologic report 7 57.1 NA NA NA 28.5 14.3
Giuliani [57] Pathologic report 26 27*

40§
53* 46* 40§ NA NA
Saitoh et al. [9] Autopsy 1828 33 7 NA 26.8 NA 20.7
Bex et al. [21] Sentinel node pilot study 8* 16 16 66.6 0 0 0
Assouad et al. [7] Autopsy 0 NA 61.5*

56.2§
7.7§ NA

* Right kidney.

§ Left kidney.

RCC=renal cell carcinoma; NA=not applicable.

Finally, in addition to such anatomic unpredictability of lymphatic outflow, another confounder is the predilection of RCC for early hematogenic dissemination without lymph node infiltration. Indeed, 57% of metastatic RCC patients (TanyM1) treated with cytoreductive nephrectomy and LND have no evidence of LNI [11] and [12], although some of those patients might have undetected lymph node metastases because of limited surgical sampling.

3.2. Imaging techniques: clinical understaging and overstaging

Available imaging techniques (ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI]) offer overall good performance in RCC diagnosis, but none is able to reliably predict nodal metastases. The smallest size for lymph node metastasis detection is 5mm at best, with a false-negative rate of 10%—a rate that becomes even higher in the presence of micrometastases [4], [13], and [14]. Enlarged hilar or retroperitoneal lymph nodes ≥2cm in diameter on CT often harbor malignancy, but this finding should be confirmed by pathologic evaluation [15]. Indeed, the available imaging technologies showed a false-positive rate of ≤60%, mainly because of reactive inflammation. In this context, Studer et al. showed that histologically positive nodes were found in only 42% of patients with enlarged nodes at preoperative CT, while the incidence of false-negative results was 4.1% [16]. Moreover, regional lymphadenopathy may be also secondary to sarcoidosis, low-grade lymphoma, and other malignancies.

New technologies, such as multidetector CT (MDCT), might result in diagnostic improvement, as shown by Catalano et al. [17]. Using MDCT, patients with suspicious lymphadenopathy at the time of nephrectomy may be identified, and the false-positive rate due to reactive hyperplasia can be reduced [17]. However, these data have to be confirmed in larger series before MDCT can be recommended as a standard preoperative imaging technique for the clinical staging of RCC. Although the superiority of MRI in the detection of lymph node involvement has been suggested [13] and [18], the role of MRI in the assessment of regional lymph nodes has not been evaluated prospectively, and no final recommendations can be made.

In the past decade, newer imaging technologies (diffusion-weighted MRI, technetium Tc 99 sentinel node technique) have been introduced as staging procedures for several solid malignancies [13] and [18]. Although diffusion-weighted imaging has been evaluated for renal mass histology [19], no data are currently available regarding its potential use in detecting small lymph node metastases. Bernie et al. developed a porcine model of RCC to test the feasibility and accuracy of sentinel node detection by an intraoperative gamma probe after injection of blue dye and technetium Tc 99m [20]. More recently, Bex et al. evaluated the feasibility of intratumoral injection of a radiolabeled tracer to image and sample the draining lymph nodes in eight patients with clinical T1–T2N0M0 RCC [21]. They relied on percutaneous intratumoral injections of technetium Tc 99m nanocolloid under ultrasound guidance followed by lymphoscintigraphy and hybrid single-proton emission CT [21]. Surgery with sampling was performed on the following day using a gamma probe and a portable mini–gamma camera. Six patients had sentinel nodes on scintigraphy (two retrocaval, four interaortocaval, and one hilar), with one extraretroperitoneal location along the internal mammary chain [21]. In two patients, exploration with the gamma probe did not reveal any radioactive hot spots. Optimization and validation of dosage of radiotracer used, injection techniques, imaging protocols, and timing to operation need to be tested in further studies. At this time, the sentinel node technique in RCC should be considered investigational.

Positron emission tomography (PET) with fluorine F 18 fluorodeoxyglucose (FDG) was tested as a potential imaging technique for detecting primary renal lesions; results were weak [22]. However, recent studies suggested combining FDG-PET with CT scanning in the detection of labeled antibodies against the carbonic anhydrase IX antigen, which has been recently proposed as a promising marker in the diagnostic process in patients with clear cell RCC [23] and [24]. Specifically, the chimeric antibody G250 (cG250) reacts against carbonic anhydrase IX, which has been demonstrated to be overexpressed in clear cell RCC. In this context, iodine I 124/cG250 PET has been shown to accurately identify clear cell RCC [25], although such a technology has not yet been proposed in the detection of RCC lymph node metastases. Finally, Guimaraes et al. pioneered the use of nanoparticle-enhanced MRI in identifying nodal involvement in patients with renal neoplasms. The protocol included T2-weighted imaging before and after administration of Ferumoxtran-10 for the prediction of LNI at nephrectomy, as well as LND [26]. However, only five RCC cases were considered, limiting the extrapolation of possible clinical implications [26].

In conclusion, the available technology is capable of accurately identifying only large lymph node metastases. At present, patients with (micro)metastases in normal-sized nodes who might benefit from LND [27] cannot be visualized by any of the above-mentioned techniques [4]. Therefore, when using the available imaging technology, the absence of any evident lymph node metastasis should not preclude the performance of a regional LND.

3.3. Lymph node invasion rates

Over the years, the incidence of nodal involvement in surgical series has been decreasing, from >30% in historical series to 3.3% in more recent studies [3], [6], and [28]. This finding may be explained by the increased ability to diagnose tumors in earlier stages and with a subsequent lower risk of nodal involvement.

First, the incidence of lymphatic metastases notably varies according to T stage and grade [29] (Table 2). The observation that LNI prevalence shows a stage-specific distribution in RCC cases was recently confirmed by a multi-institutional retrospective analysis of 3507 RCC cases [28]. The authors showed that the overall LNI prevalence across stages was 1.1%, 4.5%, and 12.3% for pT1, pT2, and pT3 cases, respectively, although the absolute numbers may be too low because not all patients underwent an extended LND. In the EORTC trial, the percentage of patients who submitted to complete LND and showed at least one lymph node metastasis was 4%, probably due to the presence of few cases with high-risk (ie, ≥T3) RCC [3]. Conversely, Schafhauser et al. reported an LNI prevalence of 14% in a cohort of RCC patients for whom the prevalence of T3–T4 cases was 58%, compared with 31% in the EORTC trial [30].

Table 2 Pathologic N1 prevalence within clinical, surgical, and pathologic features proposed as predictors of regional lymph node involvement at nephrectomy*

Variable Blute et al. [31] Capitanio et al. [28] Pantuck et al. [6] Whitson et al. [44]
pT
1 2.3 1.1 2.4 5.1
2 3.6 4.5 11.4 11.1
3–4 37.1 12.3 30.6 31.0
Fuhrman grade
I–II 0.6 NA 6.3 7.2
III–IV 8.8 NA 26.0 30.8
Symptomatic at presentation 5.2 NA NA NA
Tumor thrombus 8.8 NA NA NA
Coagulative tumor necrosis 11.1 NA NA NA
Sarcomatoid component 27.5 NA 32.3 NA

* Only series published in the last decade were considered.

NA=not applicable.

Second, the LNI prevalence is affected by tumor grade. Pantuck et al. found lymph node involvement in 6.3% of Fuhrman grade I–II tumors and in 26% of Fuhrman grade III–IV tumors [6] (Table 2).

3.4. Prognostic implications of nodal metastasis

Positive nodes have been clearly shown to have an independent adverse effect on oncologic outcome, regardless of other prognostic factors [11], [28], and [31]. The estimated cancer-specific survival (CSS) rates at 1, 5, and 10 yr following radical nephrectomy for patients with pN1 RCC are 52–72%, 21–38%, and 11–29%, respectively [28] and [31]. Patients with nodal involvement have a 7.8-fold greater chance of dying from their disease than those without nodal involvement [31]. Moreover, the presence of lymph node metastases has the strongest negative impact on CSS for patients with T1 RCC, with an intermediate effect for patients with T2–T3 RCC [28]. However, the likelihood of finding positive nodes is extremely low in those patients for whom the prognosis will be most affected by positive nodes (ie, in patients with pT1–T2 RCC) [28]. In a population-based analysis, Lughezzani et al. recently demonstrated that lymph node stage even has an impact on the survival of patients with established metastatic RCC [11]. In multivariable analyses, after adjustment for Fuhrman grade, tumor size, year of surgery, and race, the presence of lymph node metastases determined a 1.9-fold increase in the rate of cancer-specific mortality [11] at 3 yr after cytoreductive nephrectomy; the cancer-specific mortality-free rates of pN1 compared with pN0 patients were 14.4% and 34.7%, respectively [11].

The variables depicting the number of positive nodes and the nodal burden (ratio of nodes removed to total number of nodes examined) were not exhaustively tested as possible predictors of survival. In the largest study cohort reported [32], an increase in the number of positive nodes or in the nodal burden was associated with a decrease in CSS. However, although many study design flaws undermined the level of the evidences reported, after adjustment for stage, the number of positive nodes and the positive node density were not found to be independent predictors of survival [32]. In this context, Dimashkieh et al. suggested that the presence of lymph node capsule invasion, more than the number of positive nodes, may affect CSS in RCC cases [33]. The 5-yr CSS rate was 18% and 35% in patients with extracapsular nodal extension (41%) and without extracapsular nodal extension (59%), respectively (p=0.01) [33].

3.5. Can we clinically predict nodal metastases?

Clinical tools have been proposed in the last decade to predict various pathologic end points in several different settings. However, contrary to the situation with other urologic tumors, such as prostate and bladder cancer, statistical tools aiming to predict LNI have been rarely applied to RCC. Blute et al. retrospectively reviewed an institutional cohort of 1584 patients from the Mayo Clinic and developed an intraoperative nomogram to predict LNI [31]. In multivariable analyses, Fuhrman grade, tumor size, pathologic stage, sarcomatoid features, and the presence of coagulative tumor necrosis were found to be independent predictors of LNI [31]. Moreover, the authors recently confirmed their results in an updated series of high-risk RCC cases [34]. However, since the proposed nomogram lacks any external validation and requires frozen section analyses at the time of nephrectomy, its utility in daily clinical practice is limited [27].

Hutterer et al. developed a preoperative nomogram relying on age, symptoms, and tumor size to predict LNI. The nomogram was externally validated and demonstrated 78.4% accuracy [35] and [36]. Although this nomogram represents an accurate and user-friendly tool for predicting LNI in RCC, it was based on hilar LND, which does not represent the exclusive landing zone for RCC and may result in a notable underestimation of LNI risk.

Further studies aimed at identifying accurate predictors of hidden LNI, especially in low-stage disease, are mandatory to increase accuracy in predicting the presence of lymph node metastases.

3.6. When to perform a lymph node dissection

The indications for performing an LND at the time of nephrectomy are based on the available limited, evidence-based data. Overall, if radical or partial nephrectomy is planned, enlarged nodes at imaging or palpable nodes during surgery should be removed if technically feasible. At present, intraoperative frozen section and sentinel node techniques should be considered investigational for LND planning [15] and [21].

In patients with low-stage (T1–T2) RCC and clinically negative lymph nodes, LND offers extremely limited staging information and no benefit in terms of decreasing disease recurrence or improving survival (level 1 evidence) [3]. However, since no randomized trials have been able to show the value of LND in other risk categories, it cannot be concluded that LND is of no benefit in CT-negative patients.

Besides, in T1–T2 cases, if additional risk factors (sarcomatoid features, presence of coagulative tumor necrosis, and high Fuhrman grade) are present, the risk of LNI significantly increases and potentially makes LND a valid surgical addition (level 2 evidence) [6], [31], [37], [38], and [39]. In high-risk patients (cT3–T4N0 or cTanyN1), the majority of the retrospective nonrandomized trials suggest a possible benefit of regional LND on CSS [6], [31], [37], [38], and [39]. Giuliani et al. showed that the 5-yr survival rate in pN1M0 RCC cases treated with nephrectomy and extended LND was 52%, compared with 7% in patients with distant metastases [40]. Pantuck et al. showed, albeit in a univariable and underpowered analysis, that in node-positive cases, LND improved survival and produced a trend toward an improved response to immunotherapy [41]. To what extent patient selection may have influenced the results is an unquantifiable factor. However, no difference in local or systemic recurrence was observed, regardless of the extent of LND [41].

Surgery with regional LND may be considered in metastatic (M1) patients who are candidates for debulking and potential subsequent systemic treatment (level 2 evidence) [6], [31], [37], [38], and [39]. In a nonrandomized cohort of high-risk metastatic RCC patients, the National Cancer Institute analyzed 154 cases treated with cytoreductive nephrectomy in preparation for interleukin 2–based regimens [12]. Eighty-two patients with metastatic RCC and no preoperative clinically evident LNI (cN0) survived longer (median: 14.7 mo) than the 72 patients with clinically evident LNI (cN1) (median: 8.5 mo; p=0.0004) [12]. Interestingly, among patients treated with LND, no difference in survival was observed between cN1 cases treated with LND (cN1 pNany cases) and cases with pathologically confirmed N0 disease (cN0 pN0 cases), suggesting a potential benefit of LND [12]. Finally, in a nonrandomized retrospective study, probably biased by patient selection, Pantuck et al. demonstrated that the survival of metastatic RCC patients treated with cytoreductive nephrectomy is improved by performing LND at the time of surgery [41].

In summary, in high-risk (cT3–T4N0 or cN1 or cM1) patients, LND should be considered to obtain more accurate staging and because some indirect evidence exists that there may be a survival benefit (level 2 evidence). However, all the available evidence promoting the value of LND is based on retrospective, historical series (Fig. 1). The impending stage migration of RCC toward early detection will partially undermine the future applicability of such results.

gr1

Fig. 1 Rational algorithm for selection of renal cell carcinoma patient candidates for lymph node dissection (LND) at the time of radical nephrectomy. *=when technically feasible; #=palpable nodes at surgery, larger tumors, sarcomatoid features, presence of coagulative tumor necrosis, and high Fuhrman grade.

3.7. Extent of lymph node dissection: the choice of the anatomic template

No prospective study has compared lymph node metastasis detection, cancer control, and the procedural safety of performing limited versus extended LND in the RCC context. Moreover, a standardized template for LND has not been validated, and the majority of the studies available delineate only the presence or absence of a nonstandardized, surgeon-related LND. Even EORTC 30881 could not address to what extent LND should be performed, because information regarding the location and number of lymph nodes removed was lacking [3] and [4].

Although defining the optimal surgical boundaries would require a prospective comparison of various possible templates, the boundaries of an adequate LND have been suggested by anatomic studies (Table 1) and retrospective reports. According to this indirect evidence, LND should include, on the left side, para-aortic and preaortic nodes from the crus of the diaphragm to the inferior mesenteric artery and, on the right side, paracaval, retrocaval, and precaval nodes from the adrenal vein to the level of the inferior mesenteric artery (Fig. 2). Interaortocaval nodes should always be removed as well when extended LND is performed [42]. By relying on those boundaries, Schafhauser et al. reported a retrospective study comparing patients treated with nephrectomy and extended LND (group A, n=531), nephrectomy and resection of gross nodes only (group B, n=199), and nephrectomy only (group C, n=305) [30]. Although they had more unfavorable characteristics at diagnosis (prevalence of T3–T4: 58%, 51%, and 49%; G3: 30%, 25%, and 21% in groups A, B, and C, respectively), patients treated with nephrectomy and systematic extended LND showed improved 5- and 10-yr survival rates (70% and 58%, 61% and 50%, and 65% and 44%, respectively) [30]. Nevertheless, a selection bias cannot be excluded.

gr2

Fig. 2 Lymph node dissection (LND) should include (a) for the right kidney, the paracaval, retrocaval, and precaval nodes from the adrenal vein to the level of the inferior mesenteric artery, and (b) for the left kidney, the para-aortic and preaortic nodes from the crus of the diaphragm to the inferior mesenteric artery. Interaortocaval nodes (overlapping purple area) should always be removed as well when extended LND is sought.

With regard to the number of lymph nodes that should be retrieved, Terrone et al. recently analyzed in a retrospective study the impact of the number of nodes removed on the rate of nodal metastases [43]. They observed that for organ-confined and locally advanced tumors, there was a statistically significant difference in the pN+ rate between patients with <13 or ≥13 nodes examined (3.4% compared with 10.5%, and 19.7% compared with 32.2%, respectively) [43]. In the report by Schafhauser et al, the mean number of nodes removed in the group of patients treated with nephrectomy and extended lymphadenectomy was 14 [30], which was very similar to the cut-off proposed by Terrone et al. [43]. Also, Joslyn et al. found a positive correlation between the increasing number of nodes examined and the number of positive lymph nodes (r=0.12; p<0.0001) [32]. Finally, in a recent population-based cohort, Whitson et al. showed an association between increased lymph node yield and improved CSS in patients with positive lymph node nonmetastatic RCC who underwent LND. Specifically, an increase of 10 lymph nodes removed in patients with a single positive lymph node was associated with a 10% absolute increase in CSS at 5 yr (p=0.004) [44]. Although of importance, all those reports may be biased by possible surgeon-related selection in case a more extended node dissection was performed in higher-risk patients who had a higher probability of positive nodes.

Finally, because surgical approach can hamper oncologic results and LND adequacy, to date all the results supporting the role of LND in high-risk patients are not applicable to laparoscopy and robot-assisted approaches.

In conclusion, despite other urologic settings, no study found a straight correlation between number of nodes removed and CSS. Therefore, any recommendation regarding the adequate extent of LND in RCC management is based on a low level of evidence.

A challenging manipulation of the great vessels appears unavoidable when a complete LND is attempted [43], [45], [46], [47], [48], [49], and [50]. Therefore, systematic, comprehensive LND requires surgical skill and additional procedural time. Several retrospective studies, as well as the EORTC study, have shown that LND does not statistically increase the rate of complications [3], [47], [51], [52], and [53]. Only a slightly higher risk of surgical bleeding was evidenced in patients who also underwent LND [3], [47], [51], [52], and [53]. Therefore, the morbidity associated with retroperitoneal LND during nephrectomy appears to be acceptable, although the majority of studies reporting a similar rate of complications with or without LND relied on a limited LND. Patient selection, absence of prospective monitoring of possible complications, and the surgeon's expertise are additional unquantifiable factors that may have biased the results. Indeed, it is known that extensive lymphadenectomy may increase the rate of complications such as lymphoceles, chylous ascites, bleeding from lumbar or major vessels, and lesions to adjacent organs. Chyle fistula can be prevented by avoiding accidental lesion of the cisterna chyli, which is located ventral to the aorta, cephalad to the origin of the renal artery, and below the origin of the superior mesenteric artery. Some authors recommend careful inspection of the LND field to look for lymphatic or chylous leaks, with a subsequent meticulous clipping of all perihilar and retroperitoneal fibrous fatty tissue during dissection around major vessels [54] and [55]. The use of sutures may be superior to clipping to avoid the possibility of metallic clips being torn off during surgery. Moreover, sealing agents have been proposed for preventing lymphatic leaks. When unavoidable during surgery, chylous ascites can be treated by repeated paracentesis, a medium-chain triglyceride diet, salt restriction, diuretics, and bowel rest with total parenteral nutrition [54] and [55]. Surgical intervention with ligature of the leaking lymphatics is rarely needed, and only if the lymphatic leak persists despite free drainage into the abdominal cavity and maximal conservative treatment for several weeks.

3.9. Clinical research perspectives

It is hoped that the results of future prospective trials focusing on high-risk patients only will provide additional useful information regarding the need for LND. Until then, the available data from nonprospective series must be used to better define the role of LND. Finally, further efforts in the setting of targeted therapy are mandatory to delineate the impact of LND in such a scenario.

Regarding our ability to detect LNI or to identify patients who may benefit from LND, as previously discussed, standard imaging, biopsy, and available markers are currently of limited value in deciding whether to perform LND. It is hoped that upcoming trials testing the role of iodine I 124/cG250 PET and other potential newer imaging techniques will provide additional accuracy in our ability to detect nodal and distant metastases.

From a research perspective, the advent of informative biomarkers capable of discriminating between low or high risk of LNI might assist clinicians in accurate decision making. Recently, substantial progress was made in the understanding of molecular pathways that lead to nodal versus hematogenous spreading [56]. Undoubtedly, in the future, improvements in tumor molecular profiling will be as important as accurate preoperative imaging for determining an optimal treatment strategy [56].

4. Conclusions

Current imaging techniques do not allow for detection of small metastases in normal-sized lymph nodes. Large regional nodes should not necessarily be considered metastatic. The template for primary landing sites is not uniform; for the left kidney it encompasses the para-aortic and preaortic nodes from the crus of the diaphragm to the inferior mesenteric artery, and for the right kidney it encompasses the paracaval, retrocaval, and precaval nodes from the adrenal vein to the level of the inferior mesenteric artery. Interaortocaval nodes should always be removed as well when extended LND is performed.

To date, the available evidence suggests that an extended LND may be beneficial when technically feasible in patients with locally advanced disease (T3–T4) and/or unfavorable clinical and pathologic characteristics (high Fuhrman grade, larger tumors, presence of sarcomatoid features, and/or coagulative tumor necrosis). Although node-positive patients often harbor distant metastases as well, the majority of retrospective nonrandomized trials seem to suggest a possible benefit of regional LND even for this group of patients.

In patients with T1–T2, clinically negative lymph nodes and an absence of unfavorable clinical and pathologic characteristics, regional LND offers limited staging information and no benefit in terms of decreasing disease recurrence or improving survival.

Author contributions: Umberto Capitanio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Capitanio, Becker, Blute, Mulders, Patard, Russo, Studer, Van Poppel.

Acquisition of data: Capitanio, Becker, Blute, Mulders, Patard, Russo, Studer, Van Poppel.

Analysis and interpretation of data: None.

Drafting of the manuscript: Capitanio, Becker, Blute, Mulders, Patard, Russo, Studer, Van Poppel.

Critical revision of the manuscript for important intellectual content: Capitanio, Becker, Blute, Mulders, Patard, Russo, Studer, Van Poppel.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Capitanio, Becker, Blute, Mulders, Patard, Russo, Studer, Van Poppel.

Other (specify): None.

Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

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Footnotes

a University Vita-Salute San Raffaele, Department of Urology, Milan, Italy

b Boxberg Center, Department of Urology and Group Practice, Derouet/Poenicke/Becker, Boxbergweg 3, Neunkirchen/Saar, Germany

c Department of Urology, Mayo Clinic, Rochester, MN, USA

d Radboud University Medical Centre, Nijmegen, The Netherlands

e Department of Urology, CHU Bicêtre, France

f Department of Surgery, Urology Service, and Weill Medical College, Cornell University, Memorial Sloan Kettering Cancer Center, New York, NY, USA

g Department of Urology, University Hospital Bern, Bern, Switzerland

h University Hospitals Leuven, Department of Urology, Leuven, Belgium

lowast Corresponding author. San Raffaele Hospital, Urology, Via Olgettina 60, Milan, 20132, Italy. Tel. +39 0226437286; Fax: +39 0226437298.

z.star Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.